ACE inhibitors reduce mortality in patients with cardiovascular and renal disease. However, the use of ACE inhibitors is associated with the rare but potentially life-threatening side effect of angioedema. The risk of angioedema is increased 4- to 5-fold in black Americans (1.6-6.4 percent) compared to white Americans. This is a key adverse event because it may limit the use of ACE inhibitors in a population at increased risk for congestive heart failure and nephropathy. While the mechanism of ACE inhibitor-associated angioedema is not yet known, the ACE substrates bradykinin and substance P have been implicated in the pathogenesis of angioedema in animal models. Preliminary data from our laboratories suggest that, during ACE inhibition, the amino-terminal degradation of these vasoactive peptides via aminopeptidase P (APP) and dipeptidyl peptidase IV (DPPIV) is impaired in patients who develop angioedema. The purpose of the present proposal is to test the hypothesis that genetic factors that decrease degradation of bradykinin or substance P via APP or DPPIV render individuals susceptible to ACE inhibitor-associated angioedema. To do this we will first test the hypothesis that bradykinin and substance P contribute to the pathogenesis of ACE inhibitor-associated angioedema in humans, by measuring the effect of specific bradykinin B2 and substance P NK1 receptor antagonists on the duration and severity of angioedema (SPECIFIC AIM 1). Using techniques we have already developed in the study of ACE inhibitor-associated anaphylactoid reactions, we will collect pedigrees which include a proband with a history of ACE inhibitor-associated angioedema and phenotype family members according to APP and DPPIV enzyme activity and bradykinin and substance P degradation (SPECIFIC AIM 2). We will use these intermediate phenotypes to identify polymorphisms in the APP and DPPIV and other genes which may predict risk of angioedema (SPECIFIC AIM 3). In this way, this pharmacogenetic approach will provide new insight into the pathogenesis and prevention of this rare, but life-threatening, side effect of ACE inhibitors.